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Abstract: Autism spectrum disorder (ASD) is a heterogeneous neuropsychiatric condition that is often associated with severe behavioural challenges that can be as diverse in response to treatment as they are in presentation. While environmental, behavioural, communicative, therapeutic and supportive interventions are critical considerations for any individual with ASD, pharmacologic interventions are often helpful and can be necessary for improving level of functioning and quality of life. Medication treatment targets largely include frequently associated symptoms, such as irritability, or common comorbidities, such as attention deficit hyperactivity disorder (ADHD) and anxiety disorders. There is also some emerging evidence for improvement in core social impairment of ASD and some novel treatments are available, although more evidence is needed before widespread use for this indication can be recommended. In cases with symptoms refractory to first-line treatments, medications with a significant although lesser evidence base are worth consideration. It is helpful to be aware of the ever-changing treatment landscape and its potential risks and benefits when reviewing and monitoring pharmacologic options with patients and families. The goal of this review is to provide an overview of the evidence base to date for medication management of common symptom clusters in ASD, with a focus on the United States.

Original submitted: 09 February 2017; Revised submitted: 07 June 2017; Accepted for publication: 08 August 2017.

Source: Hannah Gal / Science Photo Library

People with autism spectrum disorder (ASD) tend to have problems with social interaction and communication, combined with restricted interests and rigid and repetitive behaviours.

Key points

For children with autism who suffer from impairing psychiatric symptoms, it is important to weigh up the risks and benefits of medication options as well as to optimise non-pharmacologic interventions.

Awareness of the varied strengths and limitations of the current evidence base optimally informs a discussion of medication risks and benefits.

Irritability, aggression, and self-injurious behaviour represent the most well defined symptom cluster in ASD, with risperidone and aripiprazole carrying the strongest pharmacologic evidence for this indication.

Promising preliminary studies are not yet at the point of supporting routine medication use for the core social impairment symptom cluster of autism.

Children with comorbid ASD and ADHD generally respond well to ADHD medications, though not quite as well and with higher rates of side effects than non-autistic children with ADHD; nonetheless, these classes of medications are still reasonably effective and well tolerated, and routine use in children with comorbid autism and ADHD is justified.

Introduction

Autism spectrum disorder (ASD), as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), is a neurodevelopmental disorder characterised by persistent difficulties in social communication and social interaction, coupled with restricted, repetitive patterns of behaviour or interest[1]. The Centers for Disease Control and Prevention (CDC) estimate of prevalence in the United States (US) has risen to nearly 1 in 68, with the rate varying widely depending on the community studied[2]. Additional behaviours frequently associated with ASD include aggression, self-injury and severe tantrums, which often cause families greater stress than the core features of ASD[3],[4]. Additionally, attention deficit hyperactivity disorder (ADHD) and anxiety disorders are frequently co-morbid with ASD, which can present unique challenges for diagnosis and treatment in this population[5]. The American Academy of Child and Adolescent Psychiatry recommends multidisciplinary assessment and treatment for individuals with ASD, including educational interventions, communication interventions, intensive and individualised behavioural interventions, and pharmacologic treatment for specific target symptoms or comorbidities when appropriate[6].

Challenges to pharmacologic management of behavioural symptoms in ASD include heterogeneity of presentation; high rates of psychiatric comorbidity; higher rates of adverse effects from selective serotonin reuptake inhibitors (SSRIs) and stimulants than neurotypical populations; paucity of US Food and Drug Administration (FDA) indications for medications in ASD; and difficulty in gauging treatment response and adverse effects in the context of limited communication skills, multiple informants and potential placebo-by-proxy effects[7],[8],[9],[10],[11]. Additionally, treatment-resistant aggression and irritability in individuals with ASD is relatively common, and may require referral to a tertiary care centre and treatment with multiple medications[12], including multiple antipsychotics in some cases[13].

Pharmacists can be particularly helpful to individuals with ASD, their families and their medical providers in the following ways: education of other healthcare professionals; raising awareness of drug–drug interactions, including concurrent herbal or over-the-counter medications; ensuring appropriate dosing and administration; reporting adverse drug reactions; educating on non-tablet administration options that can be critical for compliance for many patients, including patches, liquids and chewable forms; medication monitoring including reminders of when to check laboratory test results and electrocardiograms; and ensuring adherence to the clozapine Risk Evaluation and Mitigation Strategies (REMS) programme.

This article aims to briefly review the current evidence base for common medications prescribed or indicated for treatment of symptom clusters and common comorbidities of ASD with a focus on the US. Some medications that show promise for future use are also included. A comprehensive review of all medications that have been studied in autism or that have preliminary evidence for use for symptom clusters associated with autism is outside the scope of this article, and may be found in more comprehensive reviews[6],[7],[14].

Sources and selection criteria

The primary scope of this article includes randomised controlled trials (RCTs) of pharmacologic interventions for key symptom clusters in children and adolescents with ASD, focusing particularly on placebo-controlled trials in children and adolescents (Table 1). If RCTs were lacking for a medication that otherwise appears in mainstream use in treatment of patients with ASD, open-label studies were sometimes included and noted as such in the text. An initial PubMed search was conducted for RCTs in ASDs in humans written in English, using various combinations of the following search terms: ASD, autism, treatment, placebo. No age-related restriction was used in the search as the majority of the evidence was already in children and adolescents, and studies conducted in adults would still be considered for inclusion with a specifier if the general body of evidence was otherwise lacking.

Medications whose primary aim was treatment of side effects of another medication and not a key symptom cluster, such as metformin for prevention of antipsychotic-induced weight gain, were considered outside the scope of this review. Also generally excluded were studies that addressed treatment of a comorbidity in patients with ASD, such as treatment of bipolar disorder or schizophrenia in patients with ASD, as addressing all potential psychiatric comorbidities that could occur was outside the scope of the article. ADHD was an exception and was given its own section given the high rate of comorbidity, as well as some overlap in diagnostic criteria with ASD. The same rationale was used for the inclusion of anxiety disorders.

Once a particular medication was identified as appropriate for inclusion in the paper, PubMed was searched again with the initial criteria, as well as the generic name of that medication, to identify placebo-controlled RCTs pertaining to that medication that may have been missed by the original search.

Table 1: The major randomised, placebo-controlled trials (RCTs) reviewed in this article

One patient (7%) disontinued due to intolerable side effects. This patient was rehospitalised for recurrent violence after ziprasidone, a concurrent medication on which aggression had previously been stable following a previous history of hospitalisation for aggression, was decreased (connection to study medication not clear)

Dropout rate due to adverse effects (non-significantly) twice as large in placebo arms than ATX arms, suggesting a low likelihood of intolerable side effects. One seizure on ATX with another known cause, clinically felt to be unrelated to ATX

No — difference between d-cycloserine and placebo in any primary or secondary outcome; however, as published elsewhere (Wink et al. 2017), the post-treatment observation phase of the study did demonstrate significantly more gains in the DCS group than placebo group at week 22

No for primary outcome. Yes for time-by-treatment effect of ADOS restricted and repetitive behaviour score for 2.5mg dose but not placebo or 5.0mg doses

No significant difference in adverse effects between groups

None

Medications (organised by targeted symptom cluster)

Irritability, aggression and self-injurious behaviour

The irritability symptom cluster includes aggression, self-injurious behaviour and severe tantrums, which are common targets for pharmacologic management for children with ASD[15] and are often greater sources of concern than the core features of ASD[3],[4]. Behavioural interventions can help with understanding and modifying environmental triggers for such behaviour, but aggressive behaviour can also be a major safety concern that impedes participation in needed therapeutic interventions and other meaningful activities[16]. Reduction of severe irritability through pharmacologic management can be a major way to improve functioning and quality of life for a child with autism.

Second-generation antipsychotics

Risperidone and aripiprazole are the only medications currently FDA-approved for the treatment of irritability associated with ASD. Second-generation antipsychotics have a lower risk of dyskinesias than first-generation antipsychotics, and are currently considered first-line treatment for irritability and aggression in autism[17]. It should be noted that controlled studies in children are largely short-term, but that longer-term side effects of antipsychotic use can include weight gain, associated metabolic risk and extrapyramidal symptoms.

Risperidone: Risperidone is FDA-approved for the treatment of irritability in ASD. Multiple large, double-blind, placebo-controlled trials have demonstrated improvements in irritability with risperidone treatment[18],[19], including a pivotal study by the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. In this 8-week, multisite, randomised, double-blind, placebo-controlled trial in 101 children, aged 5–17 years, risperidone resulted in a large and statistically significant decrease in irritability on the Aberrant Behavior Checklist — Irritability subscale (ABC-I) compared with placebo (56.9% reduction in ABC-I with risperidone versus 14.1% reduction in ABC-I with placebo), as well as a clinical response rate of 69% with risperidone treatment versus 12% in the placebo group. Adverse effects included increased appetite, weight gain, fatigue, drowsiness, dizziness and drooling[18].

In an uncontrolled follow-up study of this pivotal RUPP trial, risperidone continued to be beneficial for treatment of irritability and other maladaptive behaviour when participants were assessed an average of 21 months after entry into the original study[20]. Weight gain, increased appetite and enuresis were also associated with longer-term use[20].

Aripiprazole: Aripiprazole is FDA-approved for treatment of irritability in youths with ASD, with two large, placebo-controlled clinical trials in children with ASD supporting its use. One trial (n=218) saw a significant reduction in ABC-I of 12.4–14.4% (depending on dose) versus an 8.4% reduction in the placebo group. The second trial (n=98) saw a significant reduction in the ABC-I of 12.9% with aripiprazole versus 5% with the placebo group. Both trials lasted 8 weeks and were in children aged 6–17 years. Sedation, weight gain and extrapyramidal symptoms were common adverse effects in both trials[21],[22]. Clinically significant prolactin elevation, a common concern with other antipsychotics, was less likely for aripiprazole than placebo in both Owen et al. and Marcus et al. (1 patient versus 3 patients and 0 patients versus 2 patients, respectively). In addition, aripiprazole was associated with a significant decrease in serum prolactin levels compared with placebo in Owen et al. (–6.3 aripiprazole versus 1.6ng/mL placebo) and Marcus et al. (–5.2–5.8ng/mL depending on dose, versus +0.9ng/mL placebo)[21],[22].

In a 52-week open-label long-term follow-up of one of these studies (n=199, youths with ASD aged 6–17 years), reductions in irritability as measured by average ABC-I scores were maintained unchanged throughout this follow-up study[23]. Aripiprazole was generally well tolerated, although weight gain, dyslipidaemia and extrapyramidal symptoms were significant concerns with long-term use[24].

In a comparison trial of aripiprazole and risperidone (n=59) in which children aged 4–18 years were randomised to either medication for 2 months of treatment, a similar reduction in the ABC-I was seen with both medications, suggesting that they are similarly effective for treatment of irritability and aggression in youth with ASD. Similar rates of adverse effects were also seen, including increased appetite, drooling and drowsiness[25]. Rates of weight gain with aripiprazole and risperidone treatment appear similar in children with ASD[26].

Paliperidone: Paliperidone is not FDA-approved to treat irritability in ASD, and placebo-controlled data are still needed, but preliminary open-label evidence is promising. In one small (n=25), 8-week open-label trial, 84% of participants clinically responded, having demonstrated improvement noted on both the Clinical Global Impression–Improvement scale (CGI-I) and the ABC-I. Paliperidone was well tolerated[27]. Weight gain and prolactin elevation was substantial, but comparable to other atypical antipsychotics[27]. In a case report, a five-year-old with ASD and severe aggression treated with paliperidone palmitate demonstrated significant improvement in aggressive behaviour with improvements noted on the ABC irritability, lethargy, stereotypy and hyperactivity subscales. The patient also had substantial weight gain, but no other notable side effects[28].

Quetiapine: There are no placebo-controlled trials of quetiapine for treatment of irritability in children with ASD, and there are minimal open-label data to support its use. In a small (n=9), 12-week open-label trial of quetiapine in boys aged 10–17 years with ASD, only two children responded with CGI scores of 1 (very much improved) or 2 (much improved), one child dropped out of the study due to worsened irritability, and another dropped out due to sedation[29]. In another small (n=11), 8-week open-label trial of quetiapine in children aged 13–17 years with ASD, aggressive behaviour significantly decreased in severity and sleep disturbances significantly improved from baseline to end point. Quetiapine was well tolerated in this trial[30].

Olanzapine: There are minimal and equivocal data to support olanzapine as a treatment option for irritability in children with ASD. A small (n=11), double-blind, placebo-controlled pilot study of olanzapine in children aged 6–14 years with ASD demonstrated a linear trend, although insignificant, toward clinical improvement on the CGI-I. Substantial weight gain was a significant adverse effect in this study. Increased appetite and sedation were also common[31]. There is also open-label evidence for improvement in irritability in a comparative effectiveness trial of olanzapine versus haloperidol in 12 youths (mean age 7.8 +/- 2.1 years) with ASD. In this trial, improvement on the CGI-I was seen in five out of six children in the olanzapine group and three out of six children in the haloperidol group[32].

Ziprasidone: Ziprasidone shows potential as a weight-neutral option for treating irritability in youths with ASD based on a small amount of open-label and retrospective evidence of effectiveness. Nine out of 12 adolescents with ASD showed clinical improvement on the CGI-I in one 6-week open-label, pilot study[33]. Significant side effects included sedation, QTc elevation and dystonic reactions. Ziprasidone did not affect weight or prolactin levels, and total cholesterol of participants decreased. QTc interval increased by a mean of 14.7ms[33]. In a retrospective, naturalistic review of 42 youths (mean age 11.8 years) with ASD and irritability who were treated with ziprasidone, the clinical response rate (based on CGI-I) was around 40%. Ziprasidone did not result in weight gain in this study either[34].

Clozapine: Prescribing and dispensing clozapine must be done through the FDA-mandated Clozapine Risk Evaluation and Mitigation Strategy (Clozapine REMS) because of the need for close monitoring for agranulocytosis. As a result of this risk, as well as other severe adverse effects such as lowered seizure threshold, cardiomyopathy and weight gain, clozapine is often reserved as a “last resort” medication. Although clozapine has excellent evidence for treatment-resistant schizophrenia[35], evidence for treatment of aggression in ASD, however promising and well tolerated, is limited to a six-patient chart review[36] and case reports/case series[37],[38],[39],[40].

Lurasidone: Lurasidone is the only atypical antipsychotic with a negative placebo-controlled trial targeting irritability in ASD. Lurasidone has been demonstrated through a 6-week, 150-patient, multi-centre, double-blind, placebo-controlled trial to not improve irritability in children and adolescents with ASD, arguing against its use for this indication[41].

First-generation antipsychotics

Haloperidol: The short-term safety and efficacy of haloperidol in youths with ASD for behavioural symptom reduction and general clinical improvement has been demonstrated in multiple placebo-controlled studies[42],[43],[44],[45], an open-label study[46] and a significant comparative effectiveness trial versus olanzapine (described above)[32]. In a notable double-blind, placebo-controlled trial of haloperidol in children aged 2.3–6.9 years with ASD (n=40), CGI-I scores were superior in haloperidol and language training versus language training alone[44]. Sedation[32],[43],[44],[45],[46] and weight gain[32] were common adverse effects, however, in general, haloperidol tended to be well tolerated overall in short-term studies. Extrapyramidal symptoms were observed as an adverse effect in two short-term studies[43],[44]. Dyskinesias and withdrawal dyskinesias have been reported with longer-term haloperidol use in children with ASD[47].

Non-antipsychotic medications

Alpha-2 agonists: Alpha-2 agonists are currently primarily used to treat hyperactivity and impulsivity in the setting of ADHD, including ADHD that is comorbid with autism; however, clonidine may play a role in treatment of irritability in some individuals with ASD[16]. In a 6-week placebo-controlled trial of clonidine in eight children (aged 5–10 years) with ASD, teacher-rated (but not clinician-rated) improvement in hyperactivity, irritability and stereotypy was noted[48]. Clonidine also correlated with small improvements in aggression in an open-label, retrospective review of 19 children with ASD[49].

Lithium: Lithium is not considered first-line treatment for ASD-associated irritability[7], but there is some evidence to support its use, particularly in the case of comorbid mood symptoms. In a retrospective chart review of youths with ASD treated as inpatients, 43% of the 30 patients studied showed significant clinical improvement. The response rate was higher (71%) for children with significant mood disorder symptoms prior to treatment, especially those more specific for bipolar disorder (mania, euphoria). Regarding tolerability, 47% of youths with ASD taking lithium reported at least one side effect[50].

There are additionally two case reports of dramatic response to lithium in adolescents with ASD and a deletion in SHANK3 on chromosome 22q13.3, associated with Phelan-McDermid Syndrome. Both patients presented with regression and catatonia-like symptoms unresponsive to benzodiazepines and returned to baseline functioning with lithium treatment[51]. Despite its promise, lithium treatment in youths is limited by the required close monitoring of therapeutic drug levels, as well as the associated risks of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism and weight gain, particularly with longer-term treatment[52].

Antiepileptics: Epilepsy is commonly comorbid in ASD and the question often arises as to whether antiepileptics may have a role in treatment of behavioural symptoms associated with the condition. A meta-analysis of seven double-blind, randomised, placebo-controlled studies of antiepileptic medications in ASD (four valproate, one lamotrigine, one levetiracetam and one topiramate) targeting irritability/aggression or global improvement demonstrated no difference between medication and placebo groups for treatment of irritability/aggression or global improvement, although it was noted that medications with diverse actions were pooled in the meta-analysis and that studies were low-powered[53]. However, the authors also note that the sparsity and small size of the anti-epileptic studies in ASD must be considered when interpreting the results of the meta-analysis[53].

Within the individual studies used in the meta-analysis, lamotrigine and levetiracetam did not separate from placebo, valproic acid yielded mixed results, and the topiramate study, an 8-week, double-blind combination study of topiramate and risperidone versus placebo and risperidone in children with autism (DSM-IV) aged 3–12 years, showed significant improvement in the topiramate combination group in several subscales of the ABC-C (community), including irritability, stereotypic behaviour and hyperactivity/noncompliance versus the control group. Somnolence and decreased appetite were more common in the topiramate group, with no significant difference in weight between the two groups at the end of the study. Topiramate had been slowly titrated with the intention of minimising the risk of cognitive side effects[54].

Valproic acid: As noted above, studies of valproate targeting irritability in ASD have produced mixed results. Valproate did not separate from a large placebo response in a randomised, double-blind, placebo-controlled trial in 30 youths (aged 6–20 years) with ASD[55]. In another randomised, double-blind, placebo-controlled trial of valproate in 27 youths (mean age 9.46 +/- 2.46, mean nonverbal IQ 63.3 +/- 23.9) with ASD with severe irritability at baseline, valproate resulted in a statistically significant improvement in irritability global clinical response. Individuals in this study were more likely to be judged valproate responders when they were found to have higher valproate blood levels: a mean of 89.77 (31.7) in responders versus 64.33 (59.3) in non-responders. Adverse events were comparable to placebo in this trial[56]. Valproate requires close monitoring for potentially severe and fatal adverse effects, including liver toxicity, hyperammonemia independent of liver function tests and pancreatitis. Generally, valproic acid is not considered a first- or second-line agent targeting irritability in persons with ASD.

N-Acetylcysteine (NAC): NAC is an antioxidant that helps glutathione formation and regulation of extracellular glutamate levels. Given mounting evidence of a possible role of glutathione deficiency and oxidative stress in ASD, there has been investigation into whether NAC may be helpful for treatment of irritability in youths with ASD. A pilot placebo-controlled trial of NAC in 29 autistic children, aged 3–10 years, showed improvement on the ABC-I. In this study, NAC was well tolerated, with only minor gastrointestinal adverse effects[57].

NAC treatment also appeared to reduce irritability as measured by the ABC-I in 2 small, double-blind, placebo-controlled trials of children with autism (aged 3.5–16 years and 4–12 years) who were already being treated with risperidone. NAC was again well tolerated in these studies[58],[59]. A recent randomised, placebo-controlled clinical trial of NAC 500g/day for 6 months in 98 children with autism did not demonstrate any difference between NAC and placebo in social responsiveness, communication or repetitive behaviour, and also no difference between NAC and placebo in adverse effects[60]. NAC has some promising evidence for improving irritability and likely does not improve social responsiveness or repetitive behaviour. Despite these findings, NAC is not considered a first- or second-agent for the treatment of ASD-associated irritability.

Naltrexone: Naltrexone is an opioid antagonist used in addictive disorders that has been studied as a potential treatment for self-injury in ASD. A systematic review of naltrexone treatment (n=127) versus placebo (n=27) in children with ASD across 10 different studies reviewed both published and unpublished clinical trials. The authors concluded that, overall, naltrexone appears to possibly improve irritability and hyperactivity in some children with ASD but does not improve the core features of the disorder. Sedation and weight loss were fairly common adverse effects, but naltrexone was well tolerated overall[61]. Generally, naltrexone is of limited potential use targeting interfering behaviour associated with ASD.

Attention-deficit hyperactivity disorder (ADHD)

ADHD is commonly comorbid with ASD and can contribute to functional impairment[5]. The two disorders have both distinct and overlapping clinical criteria and neurobiological features [62]. Targeted treatment for comorbid ADHD is often warranted, and treatment options are similar in children with and without autism. Key points of what is known of pharmacologic treatment specific to comorbid ADHD and ASD are detailed below.

Stimulants

Only the methylphenidate (MPH) class of psychostimulant medications has been well studied for treatment of ADHD symptoms in youths with ASD. Review of the placebo-controlled trials, as well as a meta-analysis, suggest that methylphenidate may be effective for treatment of ADHD symptoms in youths with comorbid ASD in nearly 50% of cases[8],[9],[63],[64]. Adverse effects in the studies included insomnia, appetite loss, irritability and social withdrawal[8],[9].

In the RUPP trial of MPH in children with autism, six of the original 72 participants discontinued the trial in the initial phase due to intolerable irritability, and 13/72 (18%) discontinued at any point for any adverse event. Irritability was a common adverse event noted in 5/66 with low dose, 8/66 with medium dose and 5/50 with high dose, versus 2/66 with placebo. Of those who completed the trial, parent-rated irritability scores did not differ between MPH and placebo[8]. Overall, response rates were lower in the RUPP trial (49% versus 77%) and adverse event discontinuation rates much higher (13% versus 1.4%) than those noted in the Multimodal Treatment Study of Children with ADHD (MTA), a major MPH trial in children with ADHD[8],[65].

Additional evidence suggests that preschoolers with ASD or intellectual disability appear to have more difficulty tolerating methylphenidate, with adverse effect rates of about 50%[66]. In children with both ASD and hyperactivity, there is some evidence for methylphenidate improving social functioning, including joint attention[67]. In a retrospective chart review, MPH appeared significantly more helpful for comorbid ADHD in children with Asperger’s syndrome (DSM-IV) than those with pervasive developmental disorder-not otherwise specified (PDD-NOS) or autistic disorder[68]. Results of stimulant trials in ASD warrant additional study to define who with ASD may best respond to this drug class, given the clearly reduced tolerability of stimulants in the ASD population compared with use in neurotypical youths.

Alpha-2-agonists

Guanfacine and clonidine are two alpha-2-agonists commonly used in the US to treat symptoms of ADHD. Although less studied in youths with ASD than methylphenidate, there is evidence supporting this class of medications for treatment of this target symptoms cluster.

Guanfacine: In a 62-patient, double-blind, multisite, placebo-controlled trial, guanfacine ER significantly improved hyperactivity in children (mean age 8.5 +/- 2.25) with ASD and corresponded with greater clinical global improvement[69]. Adverse effects included sedation and decreased appetite. Blood pressure and heart rate decreased slightly in the first four weeks of treatment and returned toward baseline by eight weeks. In a smaller double-blind, crossover study of guanfacine in 11 youths (aged 5–9 years) with comorbid ASD and ADHD, treatment resulted in significant general clinical improvement and reduction in teacher-rated hyperactivity. Drowsiness/lethargy was the most prominent adverse effect[70]. Generally, both guanfacine and guanfacine ER are commonly used agents in the treatment of ADHD in persons with ASD.

Clonidine: Evidence of clonidine’s effectiveness in youths with ASD includes an 8-patient (aged 5–10 years), placebo-controlled trial with teacher-rated (but not clinician-rated) improvement in hyperactivity, irritability and stereotypy[48]. Hypotension was the most significant reported adverse effect[48]. A retrospective review of clonidine use for treatment of sleep or behavioural problems in ASD indicated small behavioural improvement, decreased sleep initiation time and decreased frequency of nighttime awakening, according to parental report[49].

Atomoxetine: Atomoxetine has been studied for treatment of co-morbid ADHD in individuals with ASD, and appears to potentially be an effective treatment option for some individuals[64]. Three RCTs of atomoxetine in children with ASD and comorbid ADHD showed significant improvement in hyperactive symptoms, although not inattentive symptoms[71],[72],[73]. In one of these major trials (n=97, aged 6–17 years), the rates of general clinical improvement were quite low in the atomoxetine group (20.9%) and not statistically significantly greater than placebo (8.7%)[71]. Response rates were more encouraging in another trial (n=128, aged 5–14 years), with a 46.9% response rate from atomoxetine versus 16.1% from placebo[73]. Significant side effects in these studies included nausea and fatigue[71],[72],[73] and decreased appetite and delayed sleep onset[73]. In a 28-week, open-label, follow-up study (n=88, aged 6–17 years), ADHD symptoms continued to improve and adverse effects abated[74].

Repetitive behaviours

Restrictive and repetitive behaviours, interests and activities are a core symptom cluster of ASD, and can contribute to behaviour problems, difficulty with transitions and impairment of overall functioning. Few medications have shown a significant impact on this behavioural symptom cluster, although risperidone, haloperidol and atomoxetine may be helpful for some individuals. In an 8-week, double-blind, placebo-controlled trial (n=101) of risperidone targeting irritability in youths (aged 5–17 years) with ASD, significant improvement was seen in multiple secondary outcome measures of maladaptive repetitive behaviour, such as improvement in a modified Ritvo-Freeman Real Life Rating Scale subscale that focused on sensory motor behaviours (effect size 0.45), and improvement in the maladaptive behaviour domain of the Vineland Adaptive Behavior Scales (effect size 1.03)[75].

Additionally, haloperidol treatment coincided with a significant reduction in stereotypic movements in an older subset of children (aged 4.5–7.2 years) in a small, placebo-controlled trial (n=18)[45]. A placebo-controlled trial of atomoxetine for children with comorbid ASD and ADHD demonstrated improvement in the ABC stereotypic behaviour subscale[76]. A small (n=13), 8-week, double-blind, placebo-controlled trial of divalproex sodium targeting repetitive behaviours in children and one adult with autism spectrum disorders (aged 5–17 and one 40-year-old participant) demonstrated significant improvement on the CY-BOCS with a large effect size (d=1.616)[77].

SSRIs and tricyclic antidepressants appear to not have a role in addressing this symptoms cluster in youth. Cochrane reviews of randomised, placebo-controlled trials of these medication classes in ASD demonstrate that these medication classes do not improve the core features including repetitive behaviours[10],[78]. In fact, the Cochrane review of SSRIs for core features of ASD concluded that there was no clear evidence of benefit for the above indications in children, although there was some limited evidence in adults. There was emerging evidence of harm with use of SSRIs in children with ASD for these indications, as adverse effects were commonly greater than placebo despite no evidence of benefit[10]. The authors concluded that, while SSRIs do not appear to be a treatment for core features of autism, whether or not to carefully treat a co-occurring condition such as obsessive-compulsive disorder, a mood disorder or an anxiety disorder in a person with ASD could still reasonably be made on a case-by-case basis.

Valproic acid has had mixed results regarding effect on the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) in the placebo-controlled trials available to date. In one 8-week study of 13 individuals with autism (12 were ages 5–17, one was age 40; average IQ 60, range 30–104), subjects were randomised to valproic acid or placebo. Mean trough at end point was 58.23–21.63mg/ml. The study demonstrated a significant improvement in the CY-BOCS at end point, and with a large effect size of 1.616[77]. In a later, larger study in youth with ASD with severe irritability at baseline (described in the valproic acid section above), no difference in CY-BOCS scores at end point was observed between valproic acid and placebo[56].

Core social impairment

Impairment in social communication and social interaction is the major core diagnostic feature of autism, resulting in impairment of functioning and quality of life. Identifying pharmacologic interventions for core social impairment has remained a challenge, despite tremendous work done in the past decade. Recent investigations have focused on glutamatergic agents such as acamprosate (see below), memantine (see below), riluzole[79] and amantadine[80],[81], as well as GABA modulators such as arbaclofen[82],[83] and bumetanide[84] as potential treatments for ASD core social impairment via helping to restore the potential imbalance in excitatory and inhibitory neurotransmission reported in ASD. Sulforaphane, a dietary phytochemical derived from broccoli, also has some promising preliminary evidence for improving social responsiveness[85]. Further studies are needed, but preliminary studies are promising.

Memantine: Memantine may be an emerging treatment targeting social withdrawal[88], inattention[88],[89] and anxiety[88] in ASD, although results have been mixed overall[90]. In a 12-week RCT of memantine in 121 children with ASD (aged 6–12 years) with a 48-week open-label extension phase, memantine was not superior to placebo regarding improvement in social responsiveness and was actually significantly inferior to placebo in a secondary communication measure[91]. In a randomised, double-blind, placebo-controlled trial of memantine as add-on therapy to risperidone in children aged 4–12 years with ASD, treatment with memantine did not result in a significant improvement in social withdrawal or inappropriate speech, but did result in significant improvement in irritability, stereotypic behaviour and hyperactivity in the risperidone memantine group. Memantine was generally well tolerated in both studies[91],[92].

Oxytocin: The oxytocin system plays a role in human social cognition and attachment, making it a substance of great interest as potential treatment of ASD-associated core social impairment[93],[94]. Intranasal oxytocin significantly improved caregiver-rated social responsiveness (SRS-P) in 31 children with ASD (aged 3.0–8.9 years) in a placebo-controlled, randomised, clinical crossover trial[95]. Oxytocin influenced activity in brain regions implicated in social-emotional processing on neuroimaging of 16 children with ASD (mean age 13 years)[96]. Oxytocin improved performance on the Reading-the-mind-in-the-eyes test and quality of life in adults with ASD, although significant improvement was not found in primary measures of social impairment[97]. Oxytocin was well tolerated in the treatment studies[95],[97].

D-cycloserine: D-cycloserine is a partial NMDA agonist hypothesised as a potential autism treatment through regulation of glutamate neurotransmission. A small, single-blind pilot study of D-cycloserine suggested dose-related improvements in social withdrawal in 10 individuals (mean age 10 years, SD 7) with ASD[98]. A subsequent 20-patient randomised, double-blind, non-placebo-controlled trial of daily versus weekly dosing of D-cycloserine in adolescents and young adults with ASD demonstrated an average 37% reduction over time in the pooled group in the ABC subscale 3, for stereotypies and repetitive movements[99]. However, two larger randomised, double-blind, placebo-controlled trials of D-cycloserine in children with ASD failed to show any difference from placebo in any primary or secondary outcome measures of social impairment[100],[101].

A recent 10-week placebo-controlled trial of weekly social skills training immediately following a weekly D-cycloserine dose in 67 children with ASD (mean age 8.56 years, IQ>70 given the demands of social skills training) demonstrated no significant impact of D-cycloserine on social skills or any primary or secondary outcome at study conclusion; however, in this study, the Social Responsiveness Scale (SRS) raw score greatly improved in both groups, laying the groundwork for future D-cycloserine combination studies in ASD[100]. In addition, published more recently, post-treatment 22-week follow-up assessments did demonstrate more sustained social skills gains in the D-cycloserine group in follow-up on the SRS with a moderate to large effect size (P =0.003, d=0.82). Participants, caregivers and investigators had remained blinded to treatment assignment until after the 22-week assessment. A pilot eye-tracking measure was also completed at weeks 11 and 22, and demonstrated increased percent time looking at the face as a whole in the DCS group at week 22 follow-up (P <0.0001)[102].

Verbal communication

Verbal communication impairment in ASD is primarily addressed through speech therapy, alternative communication modalities and other therapeutic interventions[6]; however, impaired verbal communication may emerge as a target for pharmacologic management as well. Recent research has explored folinic acid as a potential treatment in ASD, given that cerebral folate deficiency appears relatively common in autism, and positive folate receptor-(alpha) autoantibody status may be dramatically more common in the ASD than non-ASD population[103]. In a recent randomised, double-blind, placebo-controlled trial, folinic acid supplementation was shown to significantly improve verbal communication in 48 children, aged from 3 years 4 months to 13 years 4 months, with idiopathic ASD, language impairment and positive folate receptor-(alpha) autoantibody status[103]. This work is preliminary, but future investigation of folic acid coupled with speech therapy interventions is warranted in youths with ASD and positive receptor-(alpha) autoantibody status.

Anxiety

Anxiety is a common comorbidity in ASD that can dramatically impact quality of life and overall functioning[5],[104]. A recent review of treatment of anxiety in youths with ASD notes that, to date, there are very few studies specific to treatment of anxiety in youths with ASD, and those that have been published are short-term uncontrolled studies. In two retrospective, uncontrolled, chart-review citalopram studies focusing on anxiety in ASD (n=17, aged 4–15; n=15, aged 6–16) CGI improved over time in most patients (59%; 66%), but strength of evidence was low[105],[106]. Fluvoxamine targeting various anxiety diagnoses in children with ASD did not correlate with improvement on CGI in the group as a whole in one open-label trial (n=18, aged 7–18), although it was noted that all four females in the trial were at least partial responders. Behavioural activation was common and resulted in discontinuation for three participants[107].

In an open-label study of buspirone for anxiety or irritability in children with ASD (n=22, aged 6–17), buspirone was well tolerated and benefit was unclear — 41% had a marked response and 32% had a moderate response in the CGI, with no control[108]. Buspirone was also well tolerated in a large (n=166), 24-week, placebo-controlled trial in children aged 2–6 with ASD targeting various outcome measures, with no difference in adverse effects between buspirone and placebo[109]. There remains no rigorous evidence base supporting buspirone use in ASD. In contrast to pharmacologic management, psychotherapy for anxiety appears to be about equally effective in individuals with higher-functioning ASD as those without ASD[104].

Sleep disorders

Sleep complaints are commonplace in children with ASD and appear to persist through adolescence[110]. Children with ASD also demonstrate notable differences in sleep architecture[111]. Parent training and behavioural approaches to promoting quality sleep are essential and considered first line in treatment of sleep disorders in children with ASD[112]. In conjunction with behavioural approaches, melatonin may be particularly helpful as a pharmacologic approach for insomnia in ASD[113]. Benzodiazepines and diphenhydramine can have a paradoxical effect in children with autism and worsen sleep problems[111]. Clonidine reduced parent-reported night-time awakenings and sleep initiation time in a small retrospective review in children with ASD that has been described in greater detail above[49].

Discussion

While the evidence base supporting pharmacotherapy decision-making in ASD has extensively grown in recent years, several questions remain unanswered. Among target symptoms of treatment, irritability is clearly the best defined in the field. Adequate trials of risperidone and aripiprazole are the clear first steps for treating this symptom cluster in ASD. Despite clarity regarding initial approaches to irritability treatment, the field remains unclear on best evidence-based approaches to treatment-resistant irritability. Trials of third- and fourth-line second generation antipsychotics (SGAs), use of typical antipsychotics and combination antipsychotic therapy are likely next steps in irritability treatment algorithms. The field will need to continue to explore novel pharmacotherapy approaches to irritability when first-line agents fail.

In ADHD associated with autism, it is clear that stimulants have reduced tolerability in the ASD population, yet many persons with ASD will adequately respond to this drug class. However, the field remains clearly uncertain about best-practice pharmacotherapy approaches to treating the core social impairment and repetitive behaviour associated with autism. Ongoing work to parse the heterogeneity of ASD using various means, including neuroimaging, peripheral molecular study, genetic analyses and electrophysiology, among other techniques, will be necessary in the future to define subgroups within ASD that will best respond to a particular targeted treatment that may address core ASD domains.

While a common target of treatment, anxiety remains a poorly understood ASD comorbidity without a solid evidence base for prescribing. This background likely contributes to what may be overuse of agents typically used to treat anxiety in other conditions, such as SSRIs, that have demonstrated reduced tolerability and effectiveness in persons with autism. Hopefully, significant future work will continue to better characterise ASD-associated anxiety, thus leading to rigorous clinical trials focused on this important symptom cluster.

The generally off-label nature of ASD pharmacotherapy combined with drug tolerability challenges within this population renders this area of practice challenging. In the end, all pharmacotherapy in ASD must balance medication-associated risks versus the often real and significant risks of associated interfering behaviours that commonly co-occur with the disorder.

In many cases medication management is helpful or even critical when interfering symptoms are severe or resistant to behavioural intervention in persons with ASD. Many available pharmacologic treatments for symptoms associated with ASD are currently off-label. The evolving evidence base for potential risks and benefits needs to be carefully weighed for each child’s situation. In addition, given the heterogeneity of autism, more targeted interventions are needed and may be on the horizon.

Author disclosures and conflicts of interest:

The authors report no direct conflicts of interest with this report. Logan K Wink’s current research is supported by the Simons Research Foundation, Autism Speaks, Roivant Sciences Ltd and Cures Within Reach. Wink has served as a past consultant for Otsuka. Craig A Erickson is a consultant to and holds equity in Confluence Pharmaceuticals and is a consultant to Neurotrope and Fulcrum. Erickson is a past consultant to Alcobra Pharmaceuticals, the Roche Group and Novartis. He holds non-related IP held by CCHMC and Indiana University, and receives or has received research grant support from the John Merck Fund, Indiana University School of Medicine, Cincinnati Children’s Hospital Medical Center, Autism Speaks, the United States Department of Defense, the Simons Foundation, the United States Centers for Disease Control, the National Fragile X Foundation, The Roche Group, Neuren Pharmaceuticals, the National Institutes of Health and Roivant Sciences Ltd. Kelli C Dominick, Cara M Fosdick, Lynn McClellan and Ernest V Pedapati have no conflicts to report.

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